This invention is directed at “dissolution” or “solubilization”, each of which are used interchangeably herein to refer to a dynamic process—involving the kinetics by which a material dissolves into a given media (e.g., solvent). Viewed from the perspective of the resulting solution, dissolution can be characterized by the time-rate-of-change in concentration of the sample material in the solution over a dissolution period. In contrast, “solubility” generally refers to an equilibrium condition (e.g., a thermodynamic value) and particularly refers to how much of a sample material will dissolve in a given medium under conditions in which thermodynamic equilibrium is achieved. In general, materials that have a high solubility will generally demonstrate faster dissolution than materials of lower solubility. However, dissolution characteristics are not directly and specifically correlatable to solubility, and valuable information about materials can be obtained by looking at dissolution profiles (e.g., in addition to overall solubility data).
Dissolution testing of materials is typically practiced by dissolving at least a portion of a material in a solvent to form a solution that has a varying concentration of the material over a dissolution period. Aliquots of the solution are then taken at various times during the dissolution period, and the concentration of the material in aliquot is measured. This information, taken collectively, represents a time-dependent dissolution profile. If allowed enough material and enough time to dissolve to reach saturation, one could also measure solubility. However, a dissolution profile can be determined without necessarily determining solubility. Dissolution testing is known in many fields, but is of particular significance with respect to drug candidates.
Combinatorial chemistry has revolutionized the process of drug discovery. See, for example, 29 Ace. Chem. Res. 1-170 (1996); 97 Chem. Rev. 349-509 20 (1997); S. Borman, Chem. Eng. News 43-62 (Feb. 24, 1997); A. M. Thayer, Chem. Eng. News 57-64 (Feb. 12, 1996); N. Terret, 1 Drug Discovery Today 402 (1996). Combinatorial chemistry has also been applied to materials research more generally. See, for example, U.S. Pat. No. 6,004,617 (generally), U.S. Pat. No. 5,985,356 (inorganic materials), U.S. Pat. No. 6,420,179 (organometallic materials), U.S. Pat. No. 6,346,290 (polymer materials), and U.S. Pat. No. 6,410,331 (catalyst screening) to Schultz et al. See also U.S. Pat. No. 6,514,764 (catalyst screening) to Willson.
Although combinatorial chemistry has to a great extent eliminated the bottleneck in early drug discovery, other bottlenecks have emerged in getting a new drug to market. One such bottleneck is the identification of a drug candidate that is soluble and/or that has an appropriate rate of solubilization in an aqueous solution such as water or buffered water. Low solubility and/or solubilization of a drug candidate can be problematic because it can make the drug difficult to deliver effectively in a biological system. In fact, it has been estimated that as many as thirty percent (30%) of drug candidates are discarded because they are poorly soluble (e.g., soluble to less then ten milligram per milliliter (<10 mg/ml)) and/or have poor solubilization. Drug candidates are often sent back from animal toxicology and/or clinical trials because of inability to formulate them into an acceptable delivery form (e.g., a soluble form, with appropriate solubilization characteristics).
Approaches to solve solubility and/or solubilization problems include identification of salt forms or related structures (e.g., polymorphs) of the drug candidate that may show equivalent activity and improved solubility and/or solubilization. However, such methods of identification (involving, for example, design, synthesis, and characterization of salt and polymorphic forms of a drug candidate) are generally time consuming, tedious and are by themselves bottlenecks in getting a new drug to market.
Although efforts have been made to make certain aspects of such approaches more efficient (e.g., high-throughput investigation of drug-candidate polymorphs), the current state of the art has not adequately addressed a now-evident need for a high-throughput methods and systems for determining solubilization characteristics of materials such as drug candidates. Of particular relevance, traditional methods for dissolution testing are further disadvantaged in that the dissolution screening of materials comprising drug candidate compounds is generally done with a standard USP test equipment which requires a large volume of fluid (e.g., 900 ml per sample) and a large amount of sample (e.g., 100 mg to 200 mg). See, for example, U.S. Pat. No. 4,924,716 to Schneider. The disadvantage of such known dissolution testing methods and systems is particularly evident in light of the fact that combinatorial synthesis methods generally result in new drug candidate compounds being produced only in a limited quantity during the early stage of discovery and/or lead optimization.
Accordingly, there is a need in the art to provide reliable, reproducible, high-throughput, dissolution screening methods and systems that only require a small amount of test sample.